S217: POST-TRANSPLANT NIVOLUMAB PLUS UNSELECTED AUTOLOGOUS LYMPHOCYTES IN REFRACTORY HODGKIN LYMPHOMA RESULTS IN VERY HIGH REMISSION RATE AND EXCELLENT SURVIVAL AND IT IS ASSOCIATED WITH NK CELL EXPANSION
Authors: Fabio Guolo, Paola Minetto, Silvia Pesce, Filippo Ballerini, Michele Cea, Marco Greppi, Matteo Bozzo, Maurizio Miglino, Elisabetta Tedone, Alessandra Bo, Alberto Serio, Silvia Luchetti, Simona Candiani, Marco Mora, Vanessa Agostini, Paolo Nozza, Genny Del Zotto, Emanuela Marcenaro, Roberto Massimo Lemoli
Journal: HemaSphere (2023)

Background: Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after ASCT, although only 20% complete response (CR) rate is observed. In the relapsed/refractory setting (RHL), the achievement of CR is fundamental for subsequent allogeneic stem cell transplantation (HSCT) consolidation. In order to improve the efficacy of CI in RHL, we decided to enhance early post-ASCT CI therapy with the reinfusion of unselected autologous lymphocytes infusions (ALI). The rationale of this approach consists in the achievement of a disease debulking through ASCT conditioning; the early administration of CI (nivolumab) is then performed with a minimal disease burden, alongside with the reinfusions of ALI reducing post ASCT immune depression which hamper CI efficacy. Aims: The aim of this study was to evaluate the efficacy of the procedure in terms of CR rates and overall survival (OS). Biological endpoint was to investigate the lymphocyte subpopulations involved in the mechanism of response. Methods: Patient were eligible to this study after failure to respond to first line treatment (i.e. positive PET2 or PET6 scan) and underwent autologous lymphocyte apheresis upon enrolment. All patients received conventional 2nd line chemo followed by 3rd line chemo-immunotherapy with Brentuximab-Vedotin (BV) in non-responding patients. Patient failing to achieve CR after BV were enrolled in the treatment arm and proceeded to ASCT + CI and ALI, whereas patients responding to 2nd- or 3rd treatment received ASCT followed by ALI alone, as a control cohort (figure 1A). Results: Twenty-one patients with RHL (median age 32 years; range 18-65) underwent lymphocyte apheresis after failure of 1st line chemo and then proceeded to salvage therapy. Thirteen patients failed to respond to 2nd and 3rd line therapy and thus received early post-transplant CI supported with four ALI. Eight patients responded to 2nd line chemo (n=6) or 3rd line BV (n=2) and received ASCT followed by ALI alone. No adverse events were recorded, specifically, no immune-related toxicity was observed. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR. Eight of them received HSCT consolidation. One patient refusing HSCT after achieving CR in this study relapsed and responded to CI retreatment followed by HSCT. All patients in the treatment arm are alive and disease-free after a median follow-up of 32 months (95% CI 26.4-51.0). Median disease-free survival (DFS) was not reached in treatment arm (Fig 1B). Four of the patients in the control arm relapsed (50%). Three of them responded to 3rd line therapy and proceeded to HSCT. One patient achieved CR with conventional CI treatment but refused HSCT and the other relapsing patient died because of progressive lymphoma after failure to achieve CR with conventional single agent CI. Median DFS in the control arm was 22 months (Fig 1B). Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus CI-treated patients as compared to control patients. Summary/Conclusion: Our data, with a long follow-up, show very high anti-tumour activity of ALI + CI for RHL, allowing most patients to proceed to HSCT. RHL patients in the treatment arm had an excellent outcome if compared to the control arm, which included patient who did respond to conventional treatment. Biological data suggests that this approach may accelerate NK cell development/maturation and favour the expansion of the “adaptive” NK cell compartment. Figure 1: A: Study Design Overview B: Disease Free Survival according to treatmentKeywords: Hodgkin’s lymphoma, Adoptive immunotherapy, NK cell, Autologous hematopoietic stem cell transplantation